Amevoevdanes



n t ew Paw I Z-AMINO-IN'DANES Martin Schenck, Berlin-Frohnau, andHelmer Richter,

Berlin-Grunewald, Germany, assignors to Schenng A.G., Berlin, Germany No Drawing. Filed Dec. 28, 195 5, Ser. No. 556,021 7 Claims priority, application Germany June 1 1, 1953 t 9 Claims. I cram-s71 This present invention relates to new and useful 2- amino-indane compounds and more particularly to 2- amino-indane compounds which have been found to have a good therapeutic action, particularly as analeptics, and also as analgesics and local anaesthetics.

This application is a continuation-in-part of our copending application Serial No. 434,082, filed June 2, I

1954, for Z-Amino-Indan Derivatives, now abandoned.

It is an object of the present invention to provide new 2-amino-indanes and more particularly Z-amino-indaneS carrying hydrocarbon residues as substituents in l-position and containing a keto or hydroxyl group in 3-position, and also to methods of produeing the new compounds of the present invention. a

It is another object of the presentpinve'ntionto provide new N-derivatives of the Z-amino-indanesof the present invention and methods of producing such'derivatives'.

Patented May 2 1961 ice benzyl, phenylethyl, naphthylmethyl and the like; and they may be alicyclic radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Of course these are only illustrative of the possible substituents for R and R, and other equivalent groups may be substituted therefor.

It should also be noted that either or both of the groups R and R may be alkyl, aryl, alkaryl, aralkyl or It is still another object ofthe present invention to provide new 2-amino-indan compounds, which new compound have valuable therapeutic actions, particularly as analeptics, and also an analgesics and local anaesthetics and which compounds are useful in the treatment of animals wherever the treatment calls for the use of an analeptic agent, and which also may be used in they treatment of human beings.

Other objects and advantages of the present invention 4 will be apparent from a further reading of the specification and of the appended claims.

With the above objects in view, the present invention mainly comprises as a new composition of matter, all

*ji'ndane derivative.

alicyclic radicals, but only one of the groups R may be a hydrogen atom. -It should further be noted that the groups R and'R' may be the sarneor difierent alkyl, 7

aryl, alkaryl, aralkyl and alicyclic radicals.

As stated above, the group Am maybe the amino group or -a primary or secondary amino'group, or a heterocyclic nitrogen-containing radical. Most preferably', Am is the unsubstituted amino group or is a monoor di substituted amino group substituted by alower alkyl group of not more than 4 carbon atoms. In the case of the secondary amines, the substituted alkyl groups may be the same or different groups. It is also preferred that the group Am be a saturated 5 or fi 'member heterosubsti'tuent for the hydrogen of the benzene ring such as an alkyl group e.g. methyl, ethyl, propyl, butyl, amyl, and the like, or an alkoigyl group such as methyloxy, ethyloxy, propyloxy and the like, as well as a hydroxyl radical. The production of a compound with such substituen't in the benzene ring of the 'indan system may be achieve'dby introducing the substituent into the benzene ring either before or after theformation of the amino- The production of the derivatives of the present invention may be carried out starting from indanone-3 which "ammonia or a primary or secondary amino-indane having the following structural formula:

R.- erram wherein R is selected from the group consisting of hydro gen, alkyl, aryl, alkyaryl, aralkyl and alicyclic radicalsy: where R is selected from the group consisting of alkyl, aryl, alkaryl, aralkyl and alicyclic radicals; wherein Am is "selected from the group consisting of the amino 'g roup,. mono-substituted amino groups substituted by'alkyl, aryl, aralkyl, alkaryl and alicyclic radicals, di-substituted ami-- no groups substituted by alkyl, aryl, aralkyl, alkaryl and alicyclic radicals, and 5 and 6 member saturated nitrois substituted in. the 1-position, l11 '6ltl161 of two ways:

(a) Theindanone-3 is halogenated by means ofchlorine, bromine or the -like, whereby the halogen is'introduced in 2-position, and thejhalogen is replaced'a-by amine having the formula 5 5 wherein R and R are hydrogenf'alkyl, aryl, alkaryl,

ar alkyl or alicyclic'radicals. Subsequently, the keto group in 3-positionis reduced-"seas to form the corre I sponding indanol. l

a(b)'f'Iheflindanone-3nnay beltredted with a nitrosing agent such as-nitrous acid, or a nitrite such as butyl gen-containing heterocyclic radicals linked to .therest of the molecule by the N atom; andwherein R is selected from the group consisting of hydrogen-and radicals ca-v pable of substituting for the hydrogen atom and onto a "carbon atom of the benzene ring.

The groups R and R maybe alkyl groups spch methyl, ethyl, propyl, butyl, amyl and the'like; they'inay-m. be aryl groups such as phenyl, biphenyl, naphthyl and the like; they may be alkaryl groups such as t0luyl, ethylphenyl and the like; they may be aralkyl groups suchas nitrite or-the like whereby"-the oxi rne-2:is formed and this is transformed into the 2amino compound by hydrogenation. If it is desired to retain the. keto' group in git-position, this. group is protected, for example by acetffalization, or the'isonitro'so group is subjected to suitably mild reduction conditions,--for example reduction with palladium as catalyst in the presence of hydrogen ch10 rideunder normal conditions. The alkylation of the aminoigroup may then follow in known manner for exarr'iplegby reductive alkylation or by means of the Eschyveiler-Clarke modification of the Leuckart reaction.

-' "{Ihe 'indan nucleus 'can carry further substituents as I iwellas the R and R substituents such as aryl and aralkyl groups in the 1-position of the indan molecule, fer example alkyl groups, alkoxy groups, hydroxyl groups and the like in the benzene ring of the indan nucleus.

Althoughythe present invention can result in the production of amino-ketones of the indan, the present invention is mainly interested in the production of the amino-alcohols because the amino-ketones decompose very easily. These amino-ketones easily go-over as free bases, particularly in alkaline solution wherein they are easily transformed into the pyrazine derivative. Also,

the aqueous solutions of the corresponding amino-ketonehydrochloride are extremely unstable, as may be' recognized by the discoloring and clouding within a few minutes. The corresponding amino-alcohols on the other hand are extremely stable.

In the production ofthe above mentioned :arninoalcohols, the isolation of the "amino-ketones: as intermediate product is to be avoided as much as possible. For this purpose it has been shown that when carrying out the process described under b) above, the use of activated palladium as a catalyst is an efiective means of accomplishing this result. In this manner the reduction of the keto group and the isonitroso group is carried out i a n e s ep: v

It has further been found that in this last mentioned manner of produeing the Z-amino indanol-3, it is especially advantageous to utilize the-technically most preferred nickel catalysts, especially Raney nickel, whereby the reduction may be carried out in neutral or even alkaline solution and preferably under normal conditions, e.g. withoutsuperatmosphericpressure and at room temperature.

The reaction mechanism of the process of the present invention utilizing the process under (a) or (b) above may be illustrated by the following equations:

(ail /R I v I 2R1 C NH CH-Halogen wherein R and R are either hydrogen, alkyl, aryl, aralkyl, alkaryl or alicyclic radicals, and wherein R and R may be the same or diiferent groups.

Compounds wherein the 2-position contains a monosubstituted amino group, or a di-su-bstituted amino group, or a heterocyclic nitrogen-containing radical may be produced in a similar manner.

The new compounds of the present invention have been found to exhibit an unexpectedly excellent pharmaceutical action as an analeptic agent which is marked by its absence of sympathomimetic side effects such as increase in blood pressure, etc., as compared to the known analeptic agents such as Pervitin (desoxyephedrin hydrochloride). The compounds of the present invention also have an analgesic and a local anaesthetic effect. However, their action for therapeutic purposes in both animals and human beings is of greatest importance with respectto the analeptic properties thereof. In addition to an absence of undesirable side effects such as increase of blood pressure, the compounds of the present inventionv are superior to known analeptic agents such as Pervitin in that the present :invention compounds have a much. lower toxicity.

The following are examples of the production of various compounds of the present. inventiom It is to be understood that these examples are given for illustrative purposes only, and the scope of the present invention is not meant to-be limited to the specific details of the examples,

' EXAMPLE 1 (a) The production of I-phenyle2-isonitrosoindanone- (3,) .-20.8 g. of 1-phenyl-indanone-(3), produced aocording to Auwers, Ber. d. Dtsch.Chem.Ges., 52, 110, is dissolved in 200 cc. of ether and oc.;of benzol.

a ing 5.5 g. of hydrogen chloride.

ride melting at 274280 C.

' phenyl-2-aminoindanol-( 3) may be recrystallized from di- While passing through hydrogen chloride gas, 10.8 g. of butyl nitrite are added dropwise while stirring. After a time, the isonitro-ketone precipitates-out. Thereupon an additional 100 cc. of benzol is added and the reaction mixture is cooled. There is obtained after filtering-off by suction g. of the isonitroso-ketone, having a brown color and a melting point of 202-204 C. The product can be re-crystallized from methanol whereupon it has a melting point with decomposition at 21l-.-2l2 C.

(b) Hydrogenation of 1-phenyl-2-isonitrosoindanone- (3).-The reduction of the isonitroso group can be carried out utilizing palladium as catalyst." It is possible to isolate the amino-ketone. If the catalyst is activated by the addition of palladium chloride solution, the operator is in a position to also'hydrogenate the keto group. 15

'ilf palladium chloride is added right from the beginning,

the reduction may be carried out without isolation of the amino-ketone directly to the production of the aminoalcohol. p

(c) The production of I-phenyl-Z-aminoindanone- (3)-hydrochloride.11.8 g. of 1-phenyl-2-isonitroso-indanone-(3) is dissolved in 100 cc. of methanol contain- 3 g. of palladium carbon catalyst is added and the mass is hydrogenated at room temperature and normal pressure. "After 2 hours the hydrogenation is complete. The catalyst is filtered-oil by suction and the solution is concentrated in a nitrogen atmosphere -under vacuum. The hydrochloride is precipitated-out by the addition of ether, thehydrochlo- (d) The production of 1-phnyl-2-aminoindanol-(3).- 8.3 g. of 1-phenyl-2-aminoindanone-(3)-hydrochloride is dissolved in ethanol and is hydrogenated with thepreceding catalyst by the addition of apalladium chloride solu- 5 .tion which contains 0.5 g. of palladium chloride. The

hydrogenation is completed after 2-;hours. The solution due taken up in water. The base is precipitated from the solution upon cooling by means of ammonia. The 1- oxane and has a melting point of 189-191 C. (Dioxane adheres thereto as crystalline dioxane.) The salt may be obtained from the base by treatment in the usual manner. The bitartrate melts with decompositions at 187-189 C., the neutral sulfate melts with decomposition at 219-221 C., thehydrochloride is very hygroscopic.

The following equationsillustrate the reactions in this example: 7 1

"aldehyde solution. bath for 4-5 hours.

EXAMPLE 2 p The production of l-phenyl-Z-dimethylamino-indanol- (3).4.4 g, of -l-phenyl 2 aminoindanol-(3) is mixed with 5.1 g. of 90% formic acid and 3.6 g. of 37% form- The mixture is warmed in a steam After the evolution of gas has subsided, a clear yellowish liquid results. After ending the heating, 2 g. of concentrated hydrochloric acid is added and the reaction mixture is dried under vacuum. The dried reaction mixture is then taken up in water and the solution is decolorized with activated charcoal. The base is precipitated by'nieans of ammonia and extracted with warm chloroform. The thus isolated base is rubbed with petroleum ether,;filtered-ofi by means of suction and transformed into the hydrochloride which has a melting point of 194-196 c.

The reaction mechanism is as-follows:

CH-N CH: C

1-phehyl-2-amir o-indanol-(3).;-1.3 g.- of l-phenyl-Z- 1sonitrosoindanone-(3) ishydrogenatedin 5 cc. of methanolic sodium hydroxide solution' (5 g. of 'sodium'hydroxide in 5 cc. of-iwater and 90cc. of methanol) and 5 cc'. of methanol by means of Raney nickel under normal con ditions. The hydrogentaken-up after 1 hour amounts to 0.93 of the theoretical. The hydrogenation solution after separation: is diluted with water *and filtered, the base precipitating-cut and having a melting point of 159-1631 C. The base'r'nay be recrystallized from dioxane. The melting. pointis then 162-164 C. The

diflerence in the. melting point between the product of this exampleand the product of Example l may be explained by stereoche'mistry. The yield of pure product is about of the theoretical. 1 The reaction mechanism is as follows; V

, ditions.

7 EXAMPLE 4 1phenyl-Z-aminwindqnol-(3).1.2 g. of l-phenyl-Z- isonitrosoindanone-(3) is hydrogenated in 5 cc. of methanolic sodium hydroxide solution (5 g. sodium hydroxide in 5 cc. of water and 90 cc. of methanol) and 5 cc. of methanol with Raney nickel under increased pressure of 20 atmospheres. The hydrogen taken-up after 5 minutes amounts to 0.93 of the theoretical. The hydrogenation solution is diluted with Water after separation of the catalyst, the precipitated base having a melting point of 159163 C. The base may be recrystallized from dioxane. The melting point then lies at about 162-164 C. The yield of pure compound is about 80% of the theoretical. The reaction mechanism is the. same as in the previous example, except for the use of ZOatmospheres of pressure.

EXAMPLE 5 By N-methylation in the manner described in Example 2, the l-methyl-Z-anflno-indanol-(3) can be converted to the hydrochloride of the corresponding l-methyl-Z-dimethyl-amino-indanoL-(3) which'has a melting point of 172-173 C.

EXAMPLE 6 1 -methyl-Z-aifiino-indanol-(3 -hy drchloride. -8 .8; of 1-methyl-2-isonitrosoindanone-(3 is hydrogenated-in 50 mcc..o'f methanolic sodium hydroxide solution g. sodium hydroxide in 5 cc. of Water and.,9 0 cc, of methanol) The soluand cc. of rnethanolunder normal conditions utilizing V Raneynickel as catalyst. The hydrogen take-up after 3 /4 hours amounts to 0.2 of the theoretical. The'f workingup resnlt sin the hydrochloride melting with decomposition at '234 236 C. The reaction mechanism is the same as in the preyious ex ple except that an alkaline.

solution is utilized. 1 e

I EXAMPLEVVV The formed Schifis. base precipitates first in greasy form and then gradually as a solid. The product is recrystallized from methanol and has amelting point of 142-143 C. The yield is 9.7g...

To hydrogenate the -Schifis base, 8.9 g. is dissolved A in 120 cc...o'f. dioxane. Raney nickel is utilizedascatalystand therednction is carried out under normal con- After 2 hours, the amount of hydrogen takenup amounts to'10()% of the theoretical. After this time to room temperature 200 cc. of ice water is stirred'in. V

ed from methanol-ether.

up amounts to 1 mol Hg.

period the hydrogenation is interrupted. The solution is filtered-off from the catalyst and is concentrated in vacuum. It is'then mixed with Water, the hydrogenated base is sucked-off and washed with Water. After drying over phosphorus pentoxide and potassium hydroxide there is obtained 8.7 g. of 1-phenyI-Z-benzylarnino-indanol-(3).

The melting point after recrystallization from methanol.

is 155-156 C.

5.1 g. of 1phenyl-2-benzylamino-indanol-(3) is methylated by mixing with 4.2 g. of formic acid and 1.5 g. of 38% formaldehyde. The reaction mixture is heated for 4 hours in a steam bath. This results in a strong evolution of carbon dioxide and a clear brown solyedin 70 cc. of methanol and hydrogenated at 50 C; under normal pressure utilizing. 960 mg. of palladium black as catalysts, After'3-5 minutes the hydrogen taken- The catalyst is separated by suction filtering, the solution is concentrated in-vacuum and mixed with ether. The precipitated 1 phenyl-2-' methylaminoeindanol-(3)-hydrochloride is filtered-off by suction'and washed 'withether. The yield is 4 g. The substance melts at 150-152 C. The substance dried at C. contains-V; mol of water. The free base obtained from the hydrochloride meltsat'l65-l67 C.

The reaction'mechanismof this example is as follows:

. Hooo n I GsHs I and 10cc. of toluol is then added. While thoroughly F I mixed with 150 cc. of benzol- 'Whilestirring and cooling in ice water there is introduced hydrogen chloride gas and 8 g. of butyl nitrite is slowly added dropwise. After 30 minutes it is removed from the cooling bath and i suction-filtered an additional 30 minutes whereby the H H H 1 I formed isonitroso-ketone is separated. The crystals are i washed with petroleum ether. The product melts at CH.N' Y .11 1 7- 196-198 C. 4 -CH1Q9H For reduction, 12 g. of l-phenyl-l-methyl-Z-isonitroso- 10 indanone-(E!) is mixed with 96 cc. of methanol which $11 1 contains 3.3 g. of hydrogen chloride. 2.8 g. of 10% pali. ladium carbon is utilized as catalyst. The hydrogenation is carried out under normal conditions. After the amount of hydrogen taken up which is 96% of the theoretical for 15 reduction of the isonitr'oso group, the catalyst is activated by the addition of 2.9 cc. of palladium chloride solution (10% palladium). -The hydrogenation of the keto group now commences. After an amount of hydrogen is CH.NH.CHHO1- I QENE LCH, tion remains practicallystill. The catalyst'is' then sep- H taken up which is 96.1% of the theoretical, the hydrogena- V v v p arated by suction-filtering, the solution is diluted with C y p v i 0 water and alkalized with soda solution. The precipitated base is filtered-elf by s'uctionand washed with water.

After drying in a dessicator, it is dissolved in chloroform, decoloi'ized with carbon and l-phenyl-l-methyl-Z-aminoindanol-(3)hydrochloride is precipitated by means Of etherical hydrochloric acid. The same melts at ZZZ-224 EXAMPLEs -1 phe'nyl-Z-piperidino-indanol-( 3) .'2.25 'g. of 'l-phe'nyl- 2-amino-indanol-(3) is mixed with 2.3 g. of .pentamethylene dibromide and "20 cc. of toluol (water-free). The mixture is cooked while excluding moisture fori'3 hours, Q

The reaction mechanism of-this example is 'as follows:

while stirring and refluxing. 1.7. g. of sodium bicarbonate stirring, the mixture islthenf cooked for'an additional 5-,

15"hours, under refluxing. After. cooling, -dilute sodium I 1 hydroxide and chloroform'is 'added. The chloroform- I I 1 cl 7 toluol solution is separated and washed with water. The Q t-Q chloroform-toluol solution is concentratedina steam bath v H0 f 7 v, l S Pd and'by'the :addition of etherical hydrochloricacid there 40 f C Q Q,

is precipitated 1-phenyl-2-piperidino-indanoh(3). To' re- 7 4 a l 1-phenyl-1 methy1-indianone (3), produced according to :means ofgetheri cal hydrochloric acl dissolve the same, the hydrochloride is dissolved in methanol, de-colored with carbon and mixed'with ether where-. by the hydrochloride is precipitated. Themeltingpoint of the product is 247-248 C. I T The reaction mechanism isas follows: i t I p CH3 OH-NH2' CH.NH.HO1 Pardon c j v X MPLE 10 '2 dimethylzin iino 5 .2 g; of ;formic acid. arid 3.7 g of 38%. formaldehyde' solution; The @mixturef is heated forfi hours ini a steam bath. Thisresults inastrong evolution of carbon dioxide and the reaction-mixture forms a brownish colored solution: To thissolution is"addediZ cc.iof concena on awaterbath under vacuum. The residue is dissolved in 'hotlwater and treated? with decolorizing charcoal; The

tated. The ba'se isf takefi-up finchlorqform over potassium carbonate aindtheich loroform ol tion is 'trated hydrochloric; acid and the solution is "evaporated 1 filtered solution 'is allral iied With sodafsolution- {whereby the .l-methyl-Z-dimethyl amino indanol 7, 3) is recipi-.

nw due t The'reactionmechanism of this example is as follows:

on on C/ B 3 ZHOOOH CH3 /CH.HNz--- /OHN .HCI

on gno on CH3 on H (in EXAMPLE '11 I-phenyl-S-methyl 2 amino indanol (3).29 g. of 1-phenyl-5-methyl-indanone, produced for example according to the method of Pfeitfer and Roos, Journal of Practical Chemistry, volume 159 (1941), pages 13-35, is

dissolved in 261 cc. of benzol. Under stirring and with the introduction of hydrochloric acid, 14.2 g. of butyl nitrite -is added dropwise to the solution which is cooled withice water. v v

The isonitroso ketone already starts to precipitate after about 20 minutes. j However, the react-ion is allowed to continue for still another hourto complete the conversion by after-reaction'and theprecipitate is then separated by suction and after, washed with cold benzol. The yieldis 21.2 g. of crude 1-phenyl-5-methyl-2-isonitroso-indanone- (3 the melting point is 211-212 C. with decomposition.

12.5 g. of the 1-phenyl-5-methyl-2-isonitroso-indanone- (3) is dissolved in 100 cc. of methanol which contains 5.5 g. of hydrogen chloride. 3 g. of palladium carbon is added as catalyst and the mass is hydrogenated-at room temperature and under normal pressure. When the amount of hydrogen taken up corresponds to 2 mols, the catalyst is activated by the addition of a palladium (II)- chloride solution which contains 0.78 g. of palladium (ID-chloride. The mass is then further hydrogenated whereby the ketogroup is reduced. After the hydrogenation has'come to a standstill, the solution is filtered off from the catalyst and the filtrate is concentrated'under vacuum.

The residue is taken up in water and decolorized with carbon. The 1-phenyl-5-methyl-2-amino-indanol-(3) is precipitated fromthe filtrate by the addition of ammonia solution. The base is taken up in chloroform.

After drying over calcium carbonate, the chloroform solution is concentrated considerably and thehydrochloride is precipitated by the additionof ethereal hydrochloricacid. After reprecipitationzfrom methanol-ether, the obtained 1 phenyl-S-methyl-Z-amino-indanoh(3)-hydro chloride is found to have a melting point of 232 C.

By N-metliylation according to the method described in Example 2, the lphenyl-5-methyl-2-amino-indanol-(3) can be converted to thecorresponding l-phenyl-5 methyl- Z-diniethyl;aminorindanol-(3) which has a melting point Column No,, II- ?"ve s the; s'tj'uctural formula of the compounds-listed exceptinthejcase of Pervitin which is, 'id'esoxyephediih hydrochloride. i-"fi 7 Column No: In: indicates the toxicity a the rm-- poundstested. 'This toxicity valuewas determined by finding out the dose (in milligramsper kilogram of body line givesthereference test 12 weight of the rats) at which just 50% of the animals die after intravenous (i.v.) injection of the compound.

From the literature (compare Heubner, Naunyn- Schmiedebergs Archiv, volume 202, page 594 (1943); Hauschild, Klinische Wochenschrift, volume 17, page 1257 (1938)) it is known that the toxicity determination of Pervitin show extremely dispersed values.

Column No. IV indicates the result obtained from the determination of the analeptic activity of the compounds. The measurement for the analeptic activity is based upon the Veronal (Barbital, diethylbarbituric acid) antagonism. The tests determine to what extent the effect of Veronal could be suppressed with respect'to the start of falling asleep by the pretreatment of the experimental animals (rats which had been hungered for two hours before the test) with the substance to be tested.

180 mg. of Veronal per kg. of body weight when introduced into the testing animals i-ntraperitoneally (i.p.) puts the animal to sleep within 30 minutes. If the substance to be tested has analeptic activity, the going to sleep is delayed or arrested by the application of the substance to be tested intraperitoneally 15 minutes before the giving of the Veronal. In these tests it was observed how many of the three test animals were awake 30 minutes and 60 minutes after the giving of the Veronal.

The number of animals remaining awake after 30 minutes gives the measure-for the retardation and after 60 minutes for the arresting. Column No. V gives the results of-the tests to .deter- 'mine the analgesic activityof the'compoundsset forth.

(Compare C. M. Suter,.Medicinal Chemistry, volume L, page .393, next-to-the-last paragraph No. 3, New York,

John Wiley &.Sons Inc., 1951.)

The test animal. is'placed on the heated copperplate 30 minutes and .60 minutes after the intraperitoneal injection of the substance to be tested and the time until the animal starts to run away is observed. This value is given in percent of the time which it takes an untreated animal to run away, thetime for the untreated animal being the blank time. 1 7

Column No. VI gives the values for the 'etfectof the compounds specified .onthe'blood pressure. The method used is the Trendelenburg method on cats and rabbits. These tests ascertained the level of concentration at which a change in blood pressure is just observable. In contrast to Pervitin which is known to have a sharp and prolonged blood pressure increasing effect (Hauschild.

above-cited), thecompounds of the present invention exhibit only a slight andshort blood pressure'lowering efiect. These observations, indicate a lack of 'sympathomimetic side effects for the compounds of thepresent invention. a

This was confirmed, with'fvarious tests carried-out utilizing thecompound of Example 2. These tests show the following: i

(a) In'the rabbit uterus there is an occasional irritatingeffect which however, cannot 'befinfiuenced with ergotamine; j

(b); constriction cannotbe found in the rabbits ear;

(c) No tachycardia can be observed in the isolated irog-heart; referring to Stralub (cf, Pharmakologische' Methoden Leopold Ther,: l949, s. 154 ft. Stuttgart);

reversible mydriasis; and g 1 e .In rabbits, tests in yvhich 5- 10 mg./kg. was intro- "duceds'ubcutaneously did notresult in an increase in the 1 blood sugar level. p V v 'With'humans,=after introdnction'of mg. per 10s n t hyperglycemia, or glycosuria 'couldlbe ,found;--

. The followingtab1e summarizesthe test results:.. 7

' l l 2,982,783 I 13 .14

001. 1. 061. 11 001. 111 001. IV 001. v 001. v1

' Toxicity, I Analgesic Activity Pain Conoentratlon thal Analeptie Action on 3 animals Reaction Time 1n which aflects the Dose for blood Pressure Compound v 50% in of Example Compound mg./kg. I

No. body Still awake Percent of Blank wt.- mg./kg., aftermg.lkg., after- J Iiats, Lp. Lp. mgJkg. Efiect 30 min. 60 min. 30 min. 60 mln.

' l I 90 a o 2377: (1) (3) 137. 8 60 254 221 2. 0 L

16 3 1 2405: (2).... l 86. 5 22 l 3 2 1.0 L 31 s a v I /CH: V N\ i I CH:

H .1101 l l 001. I. Col. II 001. III 001. IV CO]. V, C01. VI

Toxicity, Analgesic Activity Pain Concentration Lethal Analeptic Action onaanimais Reaction Time in which afiects the D for blood pressure Compound 50% in 1 of-Example Compound rug/kg.

No. body Still awake Percent of Blank wtumg./kg., after mg./kg., at r- Rlats, i.p. i.p. mgJkg. Efiect 30111111. 60 min. 30 min. 60 min.

2562: (11) 61 45 a s 20 229 20s 0. 25 L CH3 N CH oni 2563: (11). 3s g 12 L OH .1101 i 2482: 152.5;{ 32, 200 165 l..- L 4 on .HCl 1 v Petvitin nn v 7. 5-76 4 e 3 1 2687: (com- 97 1 0 5 266 190 1 0 L pare 2).

@ OH /CH3 N\ .HCl CH5 2512: known ass 90 1 0 19a 216 compound. g v 7 p .HOlf OH 1 L= lowering.

1 Local anesthetic action. c 1 Limited effect; close to toxicity level. Stronginerease;

Without further analysis, the:- foregoing will so fully selectedfrom the group consisting ofiwamino-indanes havreveal the gist of the present invention that others can 'ing the follojwing structural formula? by applying current knowledge readily adapt it for 'var- Y I 1 f ions applications Without omitting featnres.that ,,f rom the standpoint of prior art, fairly constitute essential-characteristics of the generic or specific aspects of this invention and, therefore, such edeptationsshould and are intended I 7 to be comprehended within the meaning and range; of R;- eqni valence of the following claims. 1' l Whzit is claimed as new and desired to be secured by Letters Patentis: p -1'.cAs a new composition of matter, anam'mo-indane ifi wherein R is selected from the group consisting of hydrogen, and lower alkyl; wherein R is selected from the group consisting of lower alkyl radicals and the phenyl radical; wherein Am is selected from the group consisting of the amino group, mono-substituted amino groups substituted by a lower alkyl radical, di-substituted amino OH groups substituted by lower alkyl radicals and 5 and 6 member saturated nitrogen-containing heterocyclic radicals linked to the rest of the molecule by the N atom;

and wherein R is selected from the group consisting of 10 CH hydrogen and lower alkyl radicals; and of acid addition 5 salts thereof.

7. As a new composition of matter, l-phenyl-Z-di- AS a new composmon of matter an ammo'mdan methylamino-indanol-(Za) having thefollowing structural having the following structural formula:

formula: R\ /R' o\ R.- CH-Am C /CHa H CH-N wherein R is a hydrogen atom; wherein R' is the phenyl C group; wherein Am is a mono-substituted amino group substituted by a lower alkyl radical; and wherein R is a hydrogen atom.

3. As a new composition of matter, an amino-indan 8. As a new composition of matter, 1-phenyl-2-methylamino-indanol-(3) having the following structural forhaving the following structural formula: mula:

R,- CH-Am as H H GENELOH,

wherein R is a hydrogen atom; wherein R is the phenyl C group; wherein Am is a di-substituted amino group sub- 40 H stituted by lower alkyl radicals; and wherein R 1s a hy- 9' As a new composition of matter 1 pheny1 1 methy1 drogen atom 2-amino-indanol-(3) having the following structural for- 4. As a new composition of matter, an amino-indan mula: having the following structural formula:

on, R.- OH-Am O CHIN 0 wherein R is a lower alkyl group; wherein R is the 4 5 phenyl group; wherein Am is the amino group; and wherein R is a hydrogen atom.

5. As a new composition of matter, an amino-indan having the following structural formula:

References Cited in the file of this patent UNITED STATES PATENTS 7 2,366,534 Kirby Ian. 2, 1945 2,441,069 Hoifmann May 4, 1948 c 7 2,578,787 Benneville Dec. 18, 1951 2,794,048 Richter May 28, 1957 FOREIGN PATENTS a; 598,124 Germany June 6, 1934 5K OTHER REFERENCES Braun, et al.: Berichte der deutschen chemischen gesellwherein R is a lower alkyl group; wherein R' is the phenyl schaft, vol. 553, pp. 3648-63, 1922.

group; wherein Am is a di-substituted amino group substituted by lower alkyl radicals; and wherein R is a hy- 7 drogen atom.

6. As a new composition of matter, 1-phenyl-2-aminoindanol- (3) having the following structural formula:

ciety, vol. 46; pp. 2093-2099, 1924.

Heinzelmann, et al.: Journal of Organic Chemistry, vol. 14, pp. 907-910, 1949.

Marvel et al.: Journal of the American Chemical Soi 

1. AS A NEW COMPOSITION OF MATTER, AN AMINO-INDANE SELECTED FROM THE GROUP CONSISTING OF AMINO-INDANES HAVING THE FOLLOWING STRUCTURAL FORMULA: 